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BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system

Mattsson, Niklas and Rajendran, Lawrence and Zetterberg, Henrik and Gustavsson, Mikael and Andreasson, Ulf and Olsson, Maria and Brinkmalm, Gunnar and Lundkvist, Johan and Jacobson, Laura and Perrot, Ludovic and Neumann, Ulf and Borghys, Herman and Mercken, Marc and Dhuyvetter, Deborah and Jeppsson, Fredrik and Blennow, Kaj and Portelius, Erik (2012) BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system. PLosOne, 7 (2). e31084-e31084. ISSN 1932-6203

Abstract

BACE1 is a key enzyme for amyloid-β (Aβ) production, and an attractive therapeutic target in Alzheimer’s disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal Aβ metabolism, inducing a unique pattern of secreted Aβ peptides. Aβ peptides were analyzed in cell media from APP transfected cells and in cerebrospinal fluid (CSF) from dogs by immunoprecipitation-mass spectrometry, using several different BACE1 inhibitors. Besides the expected reductions in Aβ1-40 and Aβ1-42, treatment also changed the relative levels of several other Aβ isoforms. In particular Aβ1-34 decreased, while Aβ5-40 increased, and these changes were more sensitive to BACE1 inhibition than the changes in Aβ1-40 and Aβ1-42. The effects on Aβ5-40 indicate the presence of a BACE1 independent pathway of Aβ degradation. The described CSF Aβ pattern may be used as a pharmacodynamic fingerprint to detect biochemical effects of BACE1-therapies in clinical trials, which might accelerate development of novel therapies.

Item Type: Article
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Keywords: β-amyloid, Alzheimer’s disease, BACE1, pharmacodynamic markers, mass spectrometry, β-secretase
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6685

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